Hydroxamic acid derivatives with tricyclic substitution

ABSTRACT

The invention provides hydroxamic acid derivatives of the general formula ##STR1## wherein R 1  represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R 2  represents a saturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring is attached via the N atom and when it is monocyclic, optionally contains NR 4 , O, S, SO or SO 2  as a ring member and/or is optionally substituted on one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl)amino, carboxy, lower alkoxycarbonyl, hydroxy-methyl, lower alkoxymethyl, carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R 3  represents a 5- or 6-membered N-heterocyclic ring which (a) is attached via the N atom, (b) optionally contains N, O and/or S, SO or SO 2  as an additional ring member, (c) is substituted by oxo on one or both C atoms adjacent to the linking N atom and (d) is optionally benz-fused or optionally substituted on one or more other C atoms by lower alkyl or oxo and/or on any additional N atom(s) by lower alkyl or aryl; R 4  represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; m stands for 1 or 2 and n stands for 1-4, pharmaceutically acceptable salts thereof, intermediates used in the manufacture thereof, and methods of use therefor. Compounds of formula I are collagenase inhibitors useful in the control or prevention of degenerative joint diseases such as rheumatoid arthritis and osteoarthritis or in the treatment of invasive tumours, atherosclerosis or multiple sclerosis.

SUMMARY OF THE INVENTION

The present invention is concerned with hydroxamic acid derivatives withtricyclic substitution.

The hydroxamic acid derivatives provided by the present invention arecompounds of the general formula ##STR2## wherein R¹ representscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

R² represents a saturated 5- to 8-membered monocyclic or bridgedN-heterocyclic ring which is attached via the N atom and whichN-heterocyclic ring, when it is monocyclic, optionally contains NR⁴, O,S, SO or SO₂ as a ring member and/or is optionally substituted on one ormore C atoms by hydroxy, lower alkyl, lower alkoxy, oxo, ketalized oxo,amino, mono(lower alkyl)amino, di(lower alkyl) amino, carboxy, loweralkoxycarbonyl, hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(loweralkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino;

R³ represents a 5- or 6-membered N-heterocyclic ring which (a) isattached via the N atom, (b) optionally contains N, O and/or S, SO orSO₂ as an additional ring member, (c) is substituted by oxo on one orboth C atoms adjacent to the linking N atom and (d) is optionallybenz-fused or optionally substituted on one or more other C atoms bylower alkyl or oxo and/or on any additional N atom(s) by lower alkyl oraryl;

R⁴ represents hydrogen, lower alkyl, aryl, aralkyl or a protectinggroup;

m stands for 1 or 2; and

n stands for 1-4;

and pharmaceutically acceptable salts thereof.

The compounds of formula I possess valuable pharmacological properties.In particular, they are collagenase inhibitors and can be used in thecontrol or prevention of degenerative joint diseases such as rheumatoidarthritis and osteoarthritis or in the treatment of invasive tumours,atherosclerosis or multiple sclerosis.

Objects of the present invention are the compounds of formula I andtheir pharmaceutically acceptable salts per se; a process for themanufacture of said compounds and salts; intermediates useful in saidprocess; and the use of said compounds and salts in the control orprevention of illnesses or in the improvement of health, especially inthe control or prevention of degenerative joint diseases or in thetreatment of invasive tumours or atherosclerosis.

DETAILED DESCRIPTION OF THE INVENTION

The hydroxamic acid derivatives provided by the present invention arecompounds of the general formula ##STR3## wherein R¹, R², R³ m and n arehereinbefore described.

As used in this Specification, the term "lower alkyl", alone or incombination, means a straight-chain or branched-chain alkyl groupcontaining a maximum of six carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.butyl, isobutyl, tert.butyl, n-pentyl,n-hexyl and the like. The term "lower alkoxy", alone or in combination,means a straight-chain or branched-chain alkoxy group containing amaximum of six carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert.butoxy and the like. The term "aryl" means anunsubstituted or substituted aromatic group, such as phenyl, which isoptionally substituted by, for example, lower alkyl, lower alkoxy and/orhalogen, i.e. fluorine, chlorine, bromine or iodine. As examples of arylgroups that may be used in accordance with this invention, p-tolyl,p-methoxyphenyl, p-chlorophenyl and the like can be enumerated. The term"aralkyl" means a lower alkyl group as hereinbefore defined in which oneor more hydrogen atoms is/are replaced by an aryl group as hereinbeforedefined. Any aralkyl can be used in accordance with this invention, suchas benzyl and the like. A ketalized oxo group can be any ketal compoundcontaining a carbon with two oxygen atoms, for example, ethylenedioxy.

A protecting group denoted by R⁴ can be any conventional protectinggroup, e.g. as known in peptide chemistry, such as benzyloxycarbonyl,tert.butoxycarbonyl, acetyl and the like.

As used in this Specification, N-heterocyclic denotes compounds havingone or more ring structures, wherein at least one ring structure isrepresented by an N atom. The term "monocyclic N-heterocyclic" denotesan N-heterocyclic group having one ring structure. As used herein theterm "bridged N-heterocyclic ring" denotes a heterocyclic ring structurecontaining at least one N atom, which is fused or bridged to at leastone additional ring structure.

Examples of monocyclic N-heterocyclic rings denoted by R² are1-pyrrolidinyl, piperidino, 1-piperazinyl, 4-aryl-1-piperazinyl,hexahydro-1-pyridazinyl, morpholino, tetrahydro-1,4-thiazin-4-yl,tetrahydro-1,4-thiazin-4-yl 1-oxide, tetrahydro-1,4-thiazin-4-yl1,1-dioxide, thiazolidin-3-yl, hexahydroazepino and octahydroazocinowhich can be substituted in the manner given earlier; for example2-(methyl-carbamoyl)-1-pyrrolidinyl, 2-(hydroxymethyl)-1-pyrrolidinyl,4-hydroxypiperidino, 2-(methylcarbamoyl)piperidino,4-hydroxyiminopiperidino, 4-methoxypiperidino, 4-methyl-1-piperazinyl,4-phenyl-1-piperazinyl, 1,4-dioxa-8-azaspiro[4.5]decan-8-yl,hexahydro-3-(methylcarbamoyl)-2-pyridazinyl,hexahydro-1-(benzyloxycarbonyl)-2-pyridazinyl,5,5-dimethyl-4-methylcarbamoyl-thiazolidin-3-yl and5,5-dimethyl-4-propylcarbamoyl-thiazolidin-3-yl.

Examples of bridged N-heterocyclic rings denoted by R² are5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.1.1]heptane,7-azabicyclo[2.2.1]-heptane, 3-azabicyclo[3.2.1]octane,2-azabicyclo[3.2.2]nonane and 3-azabicyclo[3.2.2]nonane.

Examples of N-heterocyclic rings denoted by R³ are rings of theformulae: ##STR4## in which R⁵ and R⁶ each represent hydrogen ortogether represent an additional bond or the remainder of a fusedbenzene ring;

R⁷ represents hydrogen, lower alkyl or aryl; and

X represents --CO--, --CH2--, --CH(lower alkyl)-, --C(lower alkyl)2-,--NH--, --N(lower alkyl)- or --O--; or, when R⁷ represents lower alkyland X represents --N(lower alkyl)-, the lower alkyl groups can be joinedto form a 5-, 6- or 7-membered ring;

R⁸ represents hydrogen, lower alkyl or aryl;

R⁹ and R¹⁰ each represent hydrogen or lower alkyl;

Y represents --O--, --NH-- or --N(lower alkyl)-; and

Z represents S, SO or SO₂ ;

wherein lower alkyl and aryl is as hereinbefore defined.

Examples of such N-heterocyclic ring denoted by R³ are2-oxo-1-pyrrolidinyl, 2,5-dioxo-1-pyrrolidino, phthalimido,1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl,3-methyl-2,5-dioxo-1-imidazolidinyl,3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl,2-methyl-3,5-dioxo-1,2,4-oxadiazol-4-yl,3-methyl-2,4,5-trioxo-1-imidazolidinyl,2,5-dioxo-3-phenyl-1-imidazolidinyl, 2,6-dioxopiperidino,5,5-dimethyl-2,4-dioxo-3-oxazolidinyl andhexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl.

One group of preferred compounds of formula I comprises those in whichR² represents 1-pyrrolidinyl, piperidino, 4-aryl-1-piperazino,morpholino, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thazin-4-yl1,1-dioxide, thiazolidin-3-yl, hexahydroazepino or octahydroazocinooptionally substituted on one or more C atoms by hydroxy, lower alkyl,lower alkoxy, ketalized oxo or mono(lower alkyl)-carbamoyl. Thepreferred R² is piperidino which is optionally substituted by hydroxy,particularly 4-hydroxypiperidino. Another preferred R² is3-azabicyclo[3.2.2]nonane. Also preferred are compounds of formula I inwhich R³ represents a group of formula (b), (c), or (h). When R³represents a group of formula (c), R⁷ is preferably lower alkyl and X ispreferably -C(lower alkyl)₂ -, particularly3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl. Preferably, m and n bothstand for 1.

The most preferred compounds of formula I are:

1-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine,

1-[3-cyclopropyl-2-(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol,

3-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol,

3-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane,

1-[3-cyclopentyl-2[(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol,

3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-[3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo-[3.2.2]nonaneand

1-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine.

Other preferred compounds of formula I hereinbefore are:

1-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine,

4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,

4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazineS,S-dioxide,

4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,

4-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,

3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide,

4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine,

3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide,

4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine,

4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]pyrrolidine,

8-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-1,4-dioxa-8-azaspiro[4,5]decane,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydroazocine,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine,

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepine,

1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl)-1(R orS)-(hydroxycarbamoyl)ethyl]propionyl]piperidine and

1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-phthalimidoethyl]propionyl]piperidine.

The compounds of formula I form pharmaceutically acceptable salts withbases such as alkali metal hydroxides (e.g. sodium hydroxide andpotassium hydroxide), alkaline earth metal hydroxides (e.g. calciumhydroxide and magnesium hydroxide), ammonium hydroxide and the like. Thecompounds of formula I which are basic form pharmaceutically acceptablesalts with acids. As such salts there come into consideration not onlysalts with inorganic acids such as hydrohalic acids (e.g. hydrochloricacid and hydrobromic acid), sulphuric acid, nitric acid, phosphoric acidetc, but also salts with organic acids such as acetic acid, tartaricacid, succinic acid, fumaric acid, maleic acid, malic acid, salicylicacid, citric acid, methanesulphonic acid, p-toluenesulphonic acid etc.

The compounds of formula I contain at least two asymmetric carbon atomsand can accordingly exist as optically active enantiomers, asdiastereoisomers or as racemates. The present invention is intended toembrace all of these forms.

According to the process provided by the present invention, thecompounds of formula I and their pharmaceutically acceptable salts aremanufactured by

(a) reacting an acid of the general formula ##STR5## wherein R¹, R², R³,m and n have the significance given earlier, with a compound of thegeneral formula

    H.sub.2 N-OZ                                               (III)

wherein Z represents hydrogen, tri(lower alkyl)silyl or

diphenyl(lower alkyl)silyl, and, where required, cleaving off anydiphenyl(lower alkyl)silyl group present in the reaction product, or

(b) catalytically hydrogenating a compound of the general formula##STR6## wherein R¹, R², R³, m and n have the significance given earlier

and Bz represents benzyl, and,

if desired, converting a compound of formula I obtained into apharmaceutically acceptable salt.

The reaction of an acid of formula II with a compound of formula III inaccordance with embodiment (a) of the process can be carried out in aknown manner. For example, an acid of formula II can be reacted with acompound of formula III in an inert organic solvent such asdichloromethane, dimethylformamide or the like using1hydroxybenzotriazole in the presence of a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride at about 0°C. to about room temperature. Alternatively, an acid of formula II canbe converted into the corresponding acid chloride (e.g. using oxalylchloride) and the acid chloride can then be reacted with a compound offormula III. Preferred compounds of formula III are those in which Zrepresents tert.butyldimethylsilyl or tert.butyldiphenylsilyl. When acompound of formula III in which Z represents tri(lower alkyl)silyl isused, this group is cleaved off during the reaction and working-up, anda compound of formula I is Obtained directly. On the other hand, when acompound of formula III in which Z represents diphenyl(lower alkyl)silylis used, this group remains in the reaction product and mustsubsequently be cleaved off in a known manner, for example by means offluoride ions.

The catalytic hydrogenation of a compound of formula IV in accordancewith embodiment (b) of the process can be carried out in a manner knownper se; for example in an inert organic solvent using hydrogen in thepresence of a noble metal catalyst. Suitable inert organic solvents are,for example, lower alkanols such as methanol, ethanol, etc. With respectto the catalyst, this can be, for example, a platinum, palladium orrhodium catalyst which can be supported on a suitable carrier material.Palladium-on-charcoal is the preferred catalyst. The temperature andpressure are not critical, although for convenience the catalytichydrogenation is preferably carried out at room temperature and underatmospheric pressure.

Compounds of formula I can be converted into pharmaceutically acceptablesalts by treatment with bases and basic compounds of formula I can beconverted into pharmaceutically acceptable salts by treatment withacids. Such treatments can be carried out in a conventional manner.

The acids of formula II which are used as starting materials inembodiment (a) of the process are novel and form a further object of thepresent invention.

The acids of formula II can be prepared, for example, as illustrated inthe following Reaction Scheme in which R¹, R², R³, m and n have thesignificance given earlier, Bz represents benzyl and tBu representstert-butyl: ##STR7##

Having regard to the foregoing Reaction Scheme, the individual stepsthereof can be carried out according to methods known per se. Thus, inthe first step, an amino acid of formula V, which can be obtainedaccording to the procedure described by Chenault H. K, Dahmer J. andWhitesides G. M., J. Am. Chem. Soc. 1989, 111, 6354-6364, is convertedby treatment with sodium nitrite in the presence of concentratedsulphuric acid into a hydroxy acid of formula VI which is subsequentlyreacted with benzyl bromide in the presence of an organic base, e.g. atrialkylamine such as triethylamine, into a corresponding benzyl esterof formula VII. The latter is then activated, e.g. by reaction withtrifluoromethanesulphonic anhydride, and treated with benzyl tert-butylmalonate in the presence of a strong base, e.g. an alkali metal hydridesuch as sodium hydride, to give a compound of formula VIII. Treatment ofthe latter with a strong base, e.g. an alkali metal hydride such assodium hydride, and reaction with a compound of formula IX yields adibenzyl tert-butyl butanetricarboxylate of formula X which is thendebenzylated by catalytic hydrogenation, e.g. in the presence of apalladium catalyst such as palladium-on-charcoal, to give a tert-butyldihydrogen butanetricarboxylate of formula XI. Decarboxylation of thiscompound, e.g. by heating in toluene with triethylamine, which may becarried out in situ, yields a tert-butyl hydrogen succinate of formulaXII which is condensed with a cyclic amine of formula XIII, e.g.according to the acid chloride method or using 1-hydroxybentriazole inthe presence of a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, to give acompound of formula XIV which is deprotected (e.g. by treatment withtrifluoroacetic acid) to give an acid of formula II.

The compounds of formula IV which are used as starting materials inembodiment (b) of the process are novel and form a further object of thepresent invention.

The compounds of formula IV can be prepared, for example, by reacting anacid of formula II with O-benzylhydroxylamine. This reaction can becarried out in a known manner, for example in an inert organic solventsuch as dichloromethane or dimethylformamide using1-hydroxybenzotriazole in the presence of a condensation agent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.

The remaining compounds which are used as intermediates or reactants inthe manufacture of the compounds of formula I are known compounds oranalogues of known compounds which can be prepared in a similar mannerto the known compounds.

As mentioned earlier, the compounds of formula I and theirpharmaceutically acceptable salts are collagenase inhibitors. The invitro collagenase inhibiting activity of the present compounds and saltscan be demonstrated by known means using collagenase obtained from aculture of human synovial fibroblasts according to the method of DayerJ-M et al., Proc. Natl. Acad. Sci. USA (1976), 73 945, followingactivation of the pro-collagenase in the conditioned medium by treatmentwith trypsin. Collagenase activity can be measured using ¹⁴ C-acetylatedcollagen type I from rat tail tendons as the substrate and employing themicrotitre plate assay method of Johnson-Wint, B, Anal. Biochem. (1980),104, 175. The IC₅₀ measured by this assay is a measure of thecollagenase inhibiting activity and is that concentration of a compoundor salt of the present invention in the enzyme digestion which reducessubstrate cleavage and solubilization to 50% of that achieved by theenzyme alone. An IC₅₀ measured means by this assay that the compound orsalt has collagenase inhibiting activity. This is true regardless of thevalue of the IC₅₀.

The results obtained in the foregoing test with representative compoundsand salts of this invention are compiled in Table I hereinafter:

                  TABLE I                                                         ______________________________________                                        Product of Example No.                                                                          IC.sub.50 (nM)                                              ______________________________________                                        2                 18.0                                                        4                 7.0                                                         5                 2.5                                                         7                 6.5                                                         9                 8.5                                                         16                4.1                                                         17                2.35                                                        23                34.0                                                        ______________________________________                                    

The compounds of formula I and their pharmaceutically acceptable saltscan be used as medicaments, for example in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragees, hard andsoft gelatine capsules, solutions, emulsions or suspensions. However,they can also be administered rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

For the manufacture of pharmaceutical preparations the compounds offormula I and their pharmaceutically acceptable salts can be formulatedwith therapeutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts can beused, for example, as such carriers for tablets, coated tablets, drageesand hard gelatine capsules. Suitable carriers for soft gelatine capsulesare, for example, vegetable oils, waxes, fats, semi-solid and liquidpolyols and the like. Depending on the nature of the active ingredientno carriers are, however, generally required in the case of softgelatine capsules. Suitable carriers for the manufacture of solutionsand syrups are, for example, water, polyols, saccharose, invert sugar,glucose and the like. Suitable carriers for the manufacture of injectionsolutions are, for example, water, alcohols, polyols, glycerine,vegetable oils and the like. Natural and hardened oils, waxes, fats,semi-liquid polyols and the like are suitable carriers for themanufacture of suppositories.

The pharmaceutical preparations can also contain preservatives,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for adjustment of the osmotic pressure buffers coatingagents or antioxidants.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically acceptable carrier as wellas a process for the manufacture of such medicaments are also objects ofthe present invention. This process comprises mixing a compound offormula I or a pharmaceutically acceptable salt thereof with atherapeutically inert carrier material and bringing the mixture into agalenical administration form.

As mentioned earlier, the compounds of formula I and theirpharmaceutically acceptable salts can be used in the control orprevention of illnesses, especially in the control or prevention ofdegenerative joint diseases or in the treatment of invasive tumours,atherosclerosis or multiple sclerosis. The dosage can vary within widelimits and will, of course, be adjusted to the individual requirementsin each particular case. In general, in the case of administration toadults, a daily dosage of from about 5 mg to about 30 mg, preferablyfrom about 10 mg to about 15 mg, should be appropriate, although theupper limit may be exceeded when this is found to be expedient. Thedaily dosage can be administered as a single dosage or in divideddosages.

The following Examples illustrate the present invention in more detail.In these Examples all temperatures are given in degrees Celsius.

EXAMPLE 1

A solution of 0.575 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidine(diastereoisomer 1) in 10 ml of ethanol was hydrogenated in the presenceof 0.4 g of 5% palladium-on-charcoal catalyst for 6 hours. The catalystwas removed by filtration and the solution was evaporated. The residuewas purified by flash chromatography on silica gel usingdichloromethane/methanol (96:4) for the elution to give 0.37 g of1-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 3.78-3.64 (m, 3H); 3.62 (dd, 1H, J=15,8); 3.49-3.41 (m, 1H);3.39 (dd, 1H, J=15,5); 3.33-3.27 (m, 1H); 2.95-2.87 (m, 1H); 2.83 (s,3H); 1.74-1.46 (m, 7H); 1.33 (s, 3H); 1.31 (s, 3H); 1.20-1.13 (m, 1H);0.61-0.50 (m, 1H); 0.44-0.33 (m, 2H); 0.06--0.05 (m, 2H); MS: 409(M+H)⁺.

The starting material was prepared as follows:

(i) A solution of 4.9 g of 2(R)-amino-3-cyclopropylpropionic acid(prepared in a manner analogous to that described by Chenault H. K.,Dahmer J. and Whitesides G. M. in J. Am. Chem. Soc. 1989, 111,6354-6364) in 50 ml of water containing 4.05 ml of concentratedsulphuric acid was warmed to 45°. A solution of 10.5 g of sodium nitritein 20 ml of water was added dropwise over 30 minutes. The solution wasstirred at 45° for 4 hours and then cooled to room temperature. Thesolution was extracted with three 50 ml portions of ethyl acetate. Thecombined extracts were washed with water and dried over anhydrous 30magnesium sulphate. The solvent was evaporated to leave 3.95 g of ayellow oil containing 3-cyclopropyl-2(R)-hydroxypropionic acid which wasused in the next step without further purification.

R_(f) [dichloromethane/methanol (9:1)]=0.65.

(ii) A solution of 3.95 g of the product from (i) in 50 ml of ethylacetate was treated with 5.32 ml of triethylamine and 3.8 ml of benzylbromide. The mixture was stirred and heated under reflux for 3 hours,then allowed to cool to room temperature overnight. The suspension waswashed with 2M hydrochloric acid, water and saturated sodium chloridesolution. After drying over anhydrous magnesium sulphate the solvent wasevaporated. The residue was purified by flash chromatography on silicagel using hexane/ethyl acetate (2:1) for the elution to give 3.36 g ofbenzyl 3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil.

nmr (CDCl₃): 7.39-7.28 (m; 5H); 5.19 (d, 1H, J=14); 5.15 (d, 1H, J=14);4.31-4.24 (m, 1H); 2.81 (br. d, 1H); 1.69-1.54 (m, 2H); 0.87-0.74 (m,1H); 0.45-0.34 (m, 2H); 0.08--0.07 (m, 2H).

(iii) A solution of 3.36 g of the product from (ii) and 1.49 ml ofpyridine in 10 ml of dichloromethane was added dropwise to a solution of3.07 ml of trifluoromethanesulphonic anhydride in 15 ml ofdichloromethane at 0° over 30 minutes with stirring. The mixture wasstirred at 0° for 2 hours and then washed with water and saturatedsodium chloride solution. After drying over anhydrous magnesium sulphatethe solvent was evaporated to give 5.37 g of benzyl3-cyclopropyl-2(R)-trifluoromethylsulphonyloxypropionate in the form ofan orange oil which was used in the next step without furtherpurification.

R_(f) [hexane/ethyl acetate (4:1)]=0.5.

(iv) A solution of 3.8 g of benzyl tert-butyl malonate in 50 ml of1,2-dimethoxyethane was treated with 0.504 g of an 80% dispersion ofsodium hydride in mineral oil. The mixture was stirred at roomtemperature for 30 minutes and then cooled to 0°. A solution of 5.37 gof the product from (iii) in 20 ml of dichloromethane was added dropwiseat 0°. The mixture was stirred at 0° for 2 hours and then left to warmto room temperature overnight. The solvent was evaporated and theresidue was dissolved in ethyl acetate. The solution was washed withwater and saturated sodium chloride solution. After drying overanhydrous magnesium sulphate the solvent was evaporated to give 6.54 gof 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-2(R), 3(R,S),3-propanetricarboxylate as a 1:1 mixture of diastereoisomers in the formof an orange oil.

nmr (CDCl₃): 7.46-7.36 (m, 20H); 5.19-5.07 (m, 8.H); 3.89 (d, 1H, J=10);3.85 (d, 1H, J=10) 3.37-3.26 (m, 2H); 1.68-1.52 (m, 2H); 1.52-1.38 (m,2H); 1.41 (s, 9H); 1.39 (s, 9H); 0.79-0.63 (m, 2H); 0.49-0.38 (m, 4H);0.12-0.07 (m, 4H).

(v) A solution of 6.4 g of the product from (iv) in 30 ml of1,2dimethoxyethane was treated with 0.446 g of an 80% dispersion ofsodium hydride in mineral oil. The mixture was stirred at roomtemperature for 30 minutes. A solution of 3.84 g of1-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolinedione in 20 ml of1,2-dimethoxyethane was added dropwise over 15 minutes. The mixture wasstirred at room temperature for 36 hours, the solvent was evaporated andthe residue was dissolved in ethyl acetate and washed with water andsaturated sodium chloride solution. After drying over anhydrousmagnesium sulphate the solvent was evaporated. The residue was purifiedby flash chromatography on silica gel using hexane/ethyl acetate (7:3)and subsequently hexane/ethyl acetate (6:4) for the elution to give 6.4g of 2,3-dibenzyl 3-tert-butyl 1-cyclopropyl-4-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)-2(R),3(R,S),3-butanetricarboxylate as a 1:1mixture of diastereoisomers in the form of a clear oil.

nmr (CDCl₃): 7.47-7.28 (m, 20H); 5.31-5.03 (m, 8H); 4.32-4.18 (m, 4H);3.19-3.15 (m, 1H); 3.16-3.12 (m, 1H); 2.86 (s, 6H); 2.00-1.90 (m, 1H); S1.89-1.79 (m, 1H); 1.64-1.49 (m, 1H); 1.48-1.38 (m, 1H); 1.37 (s, 12H);1.36 (s, 9H); 1.32 (s, 9H); 0.9-0.8 (m, 2H); 0.41-0.3 (m, 4H); 0.15-0.05(m, 2H); 0.04--0.04 (m, 2H).

(vi) A solution of 3.0 g of the product from (v) in 30 ml of 2-propanolwas hydrogenated in the presence of 0.3 g of 5% palladium on charcoalcatalyst for 2 hours. The catalyst was removed by filtration and thesolution was evaporated. The residue was re-evaporated from 20 mltoluene and then dissolved in 50 ml of toluene. The solution was treatedwith 0.693 ml of triethylamine and the mixture was heated under refluxfor 2 hours. The solution was cooled to room temperature and washed with2M hydrochoric acid, water and saturated sodium chloride solution. Afterdrying over anhydrous magnesium suphate the solvent was evaporated togive 1.85 g of 4-tert-butyl hydrogen 2(R)-(cyclopropylmethyl)-3(R orS)-[(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)methyl]succinate as anapproximately 6:1 mixture of diastereoisomers in the form of a yellowoil.

MS: 383 (M+H)⁺ ;

R_(f) [dichloromethane/methanol (9:1)]-0.41.

(vii) A solution of 1.0 g of the product from (vi) in 10 ml ofdichloromethane was cooled to 0° and treated in succession with 0.665 mlof N-ethylmorpholine, 0.481 g of 1-hydroxybenzotriazole and 0.602 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixturewas stirred at 0° for 30 minutes and then treated with 0.517 ml ofpiperidine. The solution was left to warm to room temperature and wasstirred overnight. The solution was washed with 5% aqueous sodiumhydrogen carbonate solution, 2M hydrochloric acid and saturated sodiumchloride solution. After drying over anhydrous magnesium sulphate thesolvent was evaporated to give 1.01 g of of 1-[2(R)-[1(R orS)-(tert-butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidineas an approximately 6:1 mixture of diastereoisomers in the form of ayellow gum.

MS: 450 (M+H)⁺ ;

R_(f) [dichloromethane/methanol (95:5)]=0.51.

(viii) A solution of 1.0 g of the product from (vii) in 2 ml oftrifluoroacetic acid was stirred at room temperature for 2.5 hours. Thesolvent was evaporated and the residue was re-evaporated from toluene.The residue was dissolved in diethyl ether and the solution wasextracted with two portions of 5% aqueous sodium hydrogen carbonatesolution. The combined extracts were acidified to pH 2 with concentratedhydrochloric acid and the product was extracted with two portions ofdichloromethane. The combined organic extracts were washed with waterand saturated sodium chloride solution and dried over anhydrousmagnesium sulphate. The solvent was evaporated to give 0.634 g of awhite foam containing 1-[2(R)-[1(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidineas a 6:1 mixture of diastereoisomers which was used in the next stepwithout further purification.

R_(f) [dichloromethane/methanol (9:1)]=0.31.

(ix) A solution of 0.634 g of the product from (viii) in 10 ml ofdichloromethane was cooled at 0°. The solution was treated in successionwith 0.41 ml of N-ethylmorpholine, 0.296 g of 1-hydroxybenzotriazole and0.371 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.The mixture was stirred at 0° for 30 minutes. A solution of 0.238 g ofO-benzylhydroxylamine in 2 ml of dichloromethane was added. The mixturewas left to warm to room temperature and was stirred overnight. Thesolution was washed with two portions of 5% aqueous sodium hydrogencarbonate solution and subsequently with 2M hydrochloric acid, water andsaturated sodium chloride solution. After drying over anhydrousmagnesium sulphate, the solvent was removed by evaporation. The residuewas purified by flash chromatography on silica gel usingdichloromethane/methanol (98:2) for the elution to give 0.592 g of1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]piperidine(diastereoisomer 1) as a white foam.

nmr (MeOD): 7.45-7.31 (m, 5H); 4.87 (d, 1H, J=13); 4.79 (d, 1H, J=13);3.78-3.65 (m, 3H); 3.63 (dd, 1H, J=15, 8); 3.53-3.45 (m, 1H); 3.44 (dd,1H, J=15,5); 3.34-3.27 (m, 1H); 2.87 (s, 3H); 2.84-2.78 (m, 1H);1.78-1.49 (m, 7H); 1.49-1.40 (m, 1H); 1.36 (s, 3H); 1.32, (s, 3H);1.12-1.04 (m, 1H); 0.61-0.50 (m, 1H); 0.48-0.37 (m, 2H); 0.07--0.06 (m,2H). MS: 499 (M+H)⁺.

EXAMPLE 2

In a manner analogous to that described in the first paragraph ofExample 1, from 0.391 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-4-piperidinol(diastereoisomer 1), prepared in a manner analagous to that described inExample 1 (i)-(ix), there was obtained 0.33 g of1-[3-cyclopropyl-2-(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 4.22-4.02 (m, 2H); 3.90-3.81 (m, 1H); 3.69-3.56 (m, 1H);3.49-3.38 (m, 2H); 3.37-3.18 (m, 2H); 3.11-3.01 (m, 1H); 2.97-2.86 (m,1H); 2.83 (d, 3H, J=5); 2.01-1.78 (m, 2H); 1.68-1.36 (m, 3H); 1.33 (s,3H); 1.31 (d, 3H, J=5); 1.24-1.13 (m, 1H); 0.62-0.50 (m, 1H); 0.49-0.33(m, 2H); 0.09--0.05 (m, 2H); MS: 425 (M+H)⁺.

EXAMPLE 3

In a manner analogous to that described in the first paragraph ofExample 1, from 0.822 g of 3-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropyl]-3-azabicyclo[3.2.2]nonane(diastereoisomer 1), prepared in a manner analagous to that described inExample 1 (i)-(ix), there was obtained 0.496 g of3-[3-cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 4.0-3.1 (m, 5H); 3.48-3.31 (m, 2H); 2.96-2.86 (m, 1H); 2.82(s, 3H); 2.14-2.03 (m,2H); 1.80-1.68 (m, 4H); 1.68-1.53 (m, 5H); 1.32(s, 3H); 1.31 (s, 3H); 1.21-1.12 (m, 1H), 0.64-0.52 (m, 1H); 0.45-0.33(m, 2H); 0.08--0.05 (m, 2H); MS: 449 (M+H)⁺.

EXAMPLE 4

In a manner analogous to that described in the first paragraph ofExample 1, from 0.6 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]piperidine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.5 g of1-[3-cyclobutyl-2(R)-[1(R or S)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (diastereoisomer 1)in the form of a white foam.

nmr (MeOD): 3.67 (dd, 1H, J=15, 10); 3.64-3.46 (m, 4H); 3.34 (dd, 1H,J=15,8); 3.12 (td, 1H, J=13,3); 2.92-2.84 (m, 1H); 2.82 (s, 3H);2.22-2.09 (m, 1H); 2.07-1.93 (m, 2H); 1.90-1.42 (m, 12H); 1.33 (s, 3H);1.32 (s, 3H); MS: 423 (M+H)⁺.

EXAMPLE 5

In a manner analogous to that described in the first paragraph ofExample 1, from 0.4 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-piperidinol(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.294 g of1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinolin the form of a white foam.

nmr (MeOD): 4.15-4.05 (m, 1H); 4.04-3.90 (m, 1H); 3.90-3.80 (m, 1H);3.72-3.57 (m, 1H); 3.45-3.30 (m,2H); 3.18-3.06 (m, 2H); 2.94-2.85 (m,1H); 2.84 (d, 3H, J=5); 2.21-1.36 (m, 13H); 1.33 (d, 3H, J=3); 1.31 (d,3H, J=6); MS: 439 (M+H)⁺.

EXAMPLE 6

In a manner analogous to that described in the first paragraph ofExample 1, from 0.642 g of 3-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutyl]-3-azabicyclo[3.2.2]nonane(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.348 g of3-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3azabicyclo[3.2.2]nonane(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 3.92 3.83 (m, 2H); 3.76 (dd, 1H, J=15, 13); 3.67-3.57 (m,2H); 3.34 (dd, 1H, J=15,5); 3.28-3.21 (m, 1H); 2.96-2.87 (m, 1H); 2.83(s, 3H); 2.23-2.13 (m, 1H); 2.12-1.92 (m, 4H); 1.91-1.48 (m,14H); 1.35(s, 3H); 1.34 (s, 3H). MS: 463 (M+H)⁺.

EXAMPLE 7

In a manner analogous to that described in the first paragraph ofExample 1, from 0.5 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-4-piperidinol(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.4 g of1-[3-cyclopentyl-2[(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1imidazolidinyl)ethyl]propionyl]-4-piperidinol(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 4.20-4.02 (m, 2H); 3.91-3.83 (m, 1H); 3.76-3.64 (m,1H);3.48-3.32 (m, 2H); 3.26-3.08 (m, 3H); 2.05-1.42 (m, 12H); 1.38-1.25(m, 7H); 1.18-1.01 (m, 3H); MS: 453 (M+H)⁺.

EXAMPLE 8

In a manner analogous to that described in the first paragraph ofExample 1, from 0.57 g of 3-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentyl]-3-azabicyclo[3.2.2]nonane(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.48 g of3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamyl)-2-[3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-3-azabicyclo[3.2.2]nonane(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 3.88-3.67 (m, 5H); 3.39-3.31 (m, 2H); 2.92-2.85 (m, 4H);2.15-2.06 (m, 2H); 1.83-1.45 (m, 16H); 1.36-1.28 (m, 7H; 1.16-1.02 (m,2H). MS: 477 (M+H)⁺.

EXAMPLE 9

A solution of 0.421 g of an approximately 6:1 mixture of diastereoisomer1 and diastereoisomer 2 of 1-[2(R)-[1(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3cyclopentylpropionyl]piperidine,prepared in a manner analogous to that described in Example l(i)-(viii),in 10 ml of dichloromethane was cooled to 0°. The solution was treatedwith 0.211 g of 1hydroxybenzotriazole, 0.24 g of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 0.22 mlof N-methylmorpholine. The mixture was stirred at 0° for 15 minutes. Asolution of 0.295 g of O-(tert-butyldimethylsilyl)hydroxylamine and 0.22ml of N-methylmorpholine in 5 ml of dichloromethane was added. Themixture was left to warm to room temperature and was stirred overnight.The solution was washed with two portions of 5% aqueous sodium hydrogencarbonate solution and subsequently with 2M hydrochloric acid andsaturated sodium chloride solution. After drying over anhydrousmagnesium sulphate, the solvent was evaporated. The residue was purifiedby flash chromatography on silica gel using dichloromethane/methanol(96:4) for the elution to give 0.123 g of 1-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 3.74-3.66 (m, 3H); 3.53-3.45 (m, 2H); 3.34 (dd, J=14,7,1H);3.23 (dr, J=4 , 14, 1H); 2.90-2.84 (m, 4H); 1.80-1.45 (m, 14H);1.38-1.23 (m, 7H); 1.15-1.01 (m, 2H); MS: 437 (M+H)⁺.

EXAMPLE 10

In a manner analogous to that described in the first paragraph ofExample 1, starting from 0.328 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclohexylpropionyl]piperidine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.269 g of1-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 3.87-3.77 (m, 2H); 3.7 (dd, J=14,9,1H); 3.64-3.56 (m, 2H);3.38-3.28 (m, 2H); 2.9-2.83 (m, 4H); 1.84-1.45 (m, 12H); 1.35 (s, 3H);1.33 (s, 3H); 1.25-1.05 (m, 5H); 0.98-0.78 (m, 2H). MS: 451 (M+H)⁺.

EXAMPLE 11

In a manner analogous to that described in Example 9, starting from 0.8g of 1-[2(R)-[1(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-tetrahydro-1,4-thiazine(diastereoisomer 1), prepared in a manner analogous to Example 1(i)-(viii), there was obtained 0.3 g of 4-[3-cyclopentyl-2(R)-[1-(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine(diastereoisomer 1) in the form of a white foam.

nmr (MeOD): 4.02-3.96 (m, 2H); 3.92-3.85 (m, 2H); 3.7 (dd, J=13,9,1H);3.37 (dd. J=13,6,1H); 3.25-3.18 (m, 1H); 2.9-2.84 (m, 4H); 2.82-2.75 (m,1H); 2.7-2.55 (m, 3H); 1.78-1.45 (m, 8H); 1.35 (s, 3H); 1.34 (s, 3H);1.18-1.04 (m, 2H). MS: 455 (M+H)⁺.

EXAMPLE 12

In a manner analogous to that described in Example 1, starting from 0.3g of 4-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-tetrahydro-1,4-thiazineS,S-dioxide (diastereoisomer 1), prepared in a manner analogous to thatdescribed in Example 1 (i)-(ix), there was obtained 0.2 g of4-[3-cyclopentyl-2(R)-[1-(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazineS,S dioxide (diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 4.45-4.3 (m, 2H); 4.0-3.93 (m, 1H); 3.78-3.65 (m, 2H);3.55-3.39 (m, 2H); 3.30-3.21 (m, 2H); 3.14-3.03 (m, 2H); 2.9-2.85 (m,4H); 1.78-1.45 (m, 9H); 1.36 (s, 3H); 1.34 (s, 3H); 1.18-1.0 (m, 2H).MS: 487 (M+H)⁺.

EXAMPLE 13

In a manner analogous to that described in Example 9, starting from 0.8g of 1-[2(R)-[1(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-tetrahydro-l,4-thiazine(diastereoisomer 1), prepared in a manner analogous to Example 1(i)-(viii), there was obtained 0.24 g of 4-[3-cyclobutyl-2(R)-[1-(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1 imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4-thiazine (diastereoisomer 1) in theform of a white solid.

nmr (MeOD): 3.98-3.75 (m, 4H); 3.64 (dd, J=13,8,1H); 3.35 (dd,J=15,6,1H); 3.07 (td, J=10,4,1H); 2.9-2.83 (m, 1H); 2.82 (s, 3H);2.78-2.72 (m, 1H); 2.66-2.52 (m, 3H); 2.18-2.08 (m, 1H); 2.05-1.93 (m,2H); 1.85-1.45 (m, 6H); 1.13 (s, 3H); 1.11 (s, 3H). MS: 441 (M+H)⁺.

EXAMPLE 14

In a manner analogous to that described in Example 9, starting from 1.22g of 1-[2(R)-[1-(R orS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclohexylpropionyl]-tetrahydro-1,4-thiazine(diastereoisomer 1), prepared in a manner analogous to Example 1(i)-(viii), there was obtained 0.45 g of 4-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1imidazolidinyl)ethyl]propionyl]-tetrahydro-1,4thiazine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 4.12-4.03 (m, 2H); 3.95-3.88 (m, 1H); 3.75-3.65 (m, 2H);3.38 (dd, J=14,6,1H); 2.88-2.82 (m, 4H); 2.78-2.72 (m, 1H); 2.68-2.55(m, 3H); 1.82-1.53 (m, 7H); 1.35 (s, 3H); 1.34 (s, 3H); 1.26-0.8 (m,8H); MS: 469 (M+H)⁺.

EXAMPLE 15

In a manner analogous to that described in Example 9, from 1.164 g of amixture of diastereoisomers of3-[2(R)-[1(RS)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-5,5-dimethyl-N-propyl-4(R)thiazolidinecarboxamide,prepared in a manner analogous to that described in Example 1(i)-(viii), there was obtained 0.329 g of 3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 5.09-4.72 (m, 2H); 4.51 and 4.46 (both s, total 1H); 3.84and 3.64 (both dd, J=14,8,1H); 3.40-3.05 (m, 4H); 2.90-2.73 (m, 4H);1.94-1.25 (m, 23H); 1.23-1.01 (m. 2H); 0.99-0.85 (m, 3H); MS: 554(M+H)⁺.

EXAMPLE 16

In a manner analogous to that described in the first paragraph ofExample 1, from 0.223 g of 4-[2(R)-[R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]morpholine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.112 g of4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 3.83-3.56 (m, 9H); 3.41 (dd, J=14,6, 1H); 3.19 (dr,J=4,11,1H); 2.91-2.81 (m, 4H); 1.77-1.42 (m, 8H); 1.38-1.23 (m, 7H);1.19-0.99 (m, 2H); MS: 439 (M+H)⁺.

EXAMPLE 17

In a manner analogous to that described in Example 9, from 1.289 g of amixture of diastereoisomers of3-[2(R)-[1(RS)-carboxy-2(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide (diastereoisomer 1), prepared in a manneranalogous to that described in Example 1 (i)-(viii), there was obtained0.629 g of 3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1imidazolidinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 4.09-4.51 (m, 2H); 4.47 and 4.43 (both s, total 1H); 3.82and 3.62 (both dd, J=14,10, total 1H); 3.37 and 3.17 (both dd, J=14,5,total 1H); 3.13-2.70 (m, 8H); 1.96-1.25 (m, 21H); 1.23-0.99 (m, 2H); MS:526 (M+H)⁺.

EXAMPLE 18

In a manner analogous to that described in the first paragraph ofExample 1, from 0.289 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,.5-dioxo-1-imidazolidinyl)ethyl]-3cyclobutylpropionyl]-4-phenylpiperazine(diastereoisomer 1 ), prepared in a manner analogous to that describedin Example 1 (i)-(ix), there was obtained 0.121 g of1-[3-cyclobutyl-2(R)-[1(R orS)-[(hydroxycarbamoyl)methyl]-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 7.25 (m, 2H); 7.00 (m, 2H); 6.85 (m, 1H); 3.94-3.73 (m, 4H);3.66 (dd, J=14,7,1H); 3.43 (dd, J=14,6, 1H); 3.23-3.09 (m, 4H);2.96-2.84 (m, 1H); 2.84 (s, 3H); 2.27-2.13 (m, 1H); 2.09-1.95 (m, 2H);1.90-1.48 (m, 6H); 1.35 (s, 3H); 1.34 (s, 3H); MS: 499 (M)⁺.

EXAMPLE 19

In a manner analogous to that described in the first paragraph ofExample 1, from 0.455 g of 4-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]morpholine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.194 g of4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 3.80-3.51 (m, 9H); 3.42 (dd, J=14,6,1H); 3.14-3.06 (dt,J=4,11,1H); 3.04-2.86 (m, 1H); 2.85 (s, 3H); 2.23-2.11 (m, 1H);2.06-1.95 (m, 2H); 1.91-1.73 (m, 2H); 1.71-1.46 (m, 4H); 1.35 (s, 3H);1.34 (s, 3H); MS: 425 (M)⁺.

EXAMPLE 20

In a manner analogous to that described in the first paragraph ofExample 1, from 0.625 g of 1-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3cyclobutylpropionyl]pyrrolidine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.384 g of1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 3.77-3.69 (m, 1H); 3.61 (dd, J=14,6,1H); 3.53-3.44 (m, 2H);3.39-3.31 (m, 2H); 2.93-2.85 (m, 2H); 2.84 (s, 3H); 2.26-2.13 (m, 1H);2.07-1.71 (m, 8H); 1.69-1.46 (m, 4H); 1.36 (s, 3H); 1.33 (s, 3H); MS:409 (M+H)⁺.

EXAMPLE 21

In a manner analogous to that described in the first paragraph ofExample 1, from 0.176 g of 8-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-1,4-dioxa-8-azaspiro[4,5]decane(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.084 g of8-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1imidazolidinyl)ethyl]propionyl]-1,4-dioxa-8-azaspiro[4,5]decane(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 4.02 (s, 4H); 3.81-3.60 (m, 5H); 3.99 (dd, J=14,6,1H);3.20-3.10 (m, 1H); 2.93-2.85 (m, 1H); 2.84 (s, 3H); 2.21-2.09 (m, 1H);2.06-1.93 (m, 2H); 1.80-1.46 (m, 10H); 1.35 (s, 3H); 1.33 (s, 3H); MS:481 (M+H)⁺.

EXAMPLE 22

In a manner analogous to that described in the first paragraph ofExample 1, from 0.443 g of 1-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine(diastereoisomer 1 ) there was obtained 0.319 g of1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 3.96-3.80 (m, 2H); 3.69-3.59 (m, 1H); 3.54-3.23 (m, 7H);3.18-3.09 (m, 1H); 2.93-2.80 (m, 4H); 2.21-2.09 (m, 1H); 2.07-1.41 (m,12H); 1.41-1.38 (m, 6H); MS: 453 (M+H)⁺.

The starting material was prepared as follows

(i) A solution of 0.925 g of 1-[2(R)-[1(R orS)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopropylpropionyl]-4-hydroxypiperidinein 8 ml of dimethylformamide was treated with 1.08 g of methyl iodideand 1.79 g of silver oxide. The mixture was stirred at room temperaturein the dark for 2 days. Additional portions of 0.54 g of methyl iodideand 0.895 g of silver oxide were then added and the mixture was stirredfor a further 3 days. The solvent was evaporated and the residue wassuspended in ethyl acetate and filtered. The ethyl acetate solution wasconcentrated and the residue was purified by flash chromatography onsilica gel using ethyl acetate for the elution. There was obtained 0.61g of 1-[2(R)-[1(R orS)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidinein the form of a colorless gum.

(ii) In a manner analogous to that described in Example 1 (viii)-(ix)from 0.61 g of 1-[2(R)-[1(R orS)-(tert.butoxycarbonyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4methoxypiperidinethere was obtained 0.443 g of 1-[2(R)-[1(R orS)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-4-methoxypiperidine(diastereoisomer 1) in the form of a colorless gum.

EXAMPLE 23

In a manner analogous to that described in the first paragraph ofExample 1, from 0.94 g of1-[2(R)-[1(RS)-benzyloxycarbonoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]-octahydroazocine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.663 g of1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydroazocine(diastereoisomer 1) in the form of a white solid:

nmr (MeOD): 3.77 (dd, J=14,10,1H); 3.66-3.43 (m, 4H); 3.33 (dd,J=14,5,1H); 3.07 (dt, J=10,4,1H); 2.91-2.81 (m, 4H); 2.29-2.16 (m, 1H);2.10-1.95 (m, 2H); 1.90-1.46 (m, 16H); 1.34 (s, 6H); MS: 451 (M+H)⁺.

EXAMPLE 24

In a manner analogous to that described in the first paragraph ofExample 1, from 0.37 g of 1-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]-3-cyclobutylpropionyl]piperidine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (v)-(ix) using3-(bromomethyl)-5,5-dimethyloxazolidine-2,4-dione in place of1-(bromomethyl)-3,4,4-trimethyl-2,5-imidazolinedione, there was obtained0.131 g of 1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine(diastereoisomer 1) in the form of a white solid:

nmr (MeOD): 3.72-3.53 (m, 5H): 3.39 (dd, J=14,6,1H), 3.14 (dt,J=10,4,1H); 2.95-2.86 (m, 1H); 2.23-2.11 (m, 1H); 2.08-1.94 (m, 2H);1.90-1.44 (m, 18H); MS: 410 (M+H)⁺.

EXAMPLE 25

In a manner analogous to that described in the first paragraph ofExample 1, from 0.42 g of 1-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclobutylpropionyl]hexahydroazepine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), there was obtained 0.197 g of1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepine (diastereoisomer 1) inthe form of a white solid:

nmr (MeOD): 3.77-3.64 (m, 2H); 3.62-3.45 (m, 3H); 3.33 (dd, J=14,5,1H);3.07 (dt, J=10,4,1H); 2.91-2.81 (m, 4H); 2.24-2.13 (m, 1H); 2.09-1.95(m, 2H); 1.90-1.47 (m, 14H); 1.35 (s, 3H); 1.34 (s, 3H); MS: 437 (M+H)⁺.

EXAMPLE 26

In a manner analogous to that described in the first paragraph ofExample 1, from 0.37 g of 1-[2(R)-[1(R orS)-benzyloxycarbamoyl)-2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl)ethyl]-3-cyclobutylpropionyl]piperidine(diastereoisomer 1), prepared in a manner analogous to that described inExample 1 (i)-(ix), using2-(bromomethyl)-hexahydro-l,3-dioxopyrazolo[1,2-a][1,2,4]triazole, therewas obtained 0.118 g of1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl)-1(Ror S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine in the form of awhite solid.

nmr (MeOD): 3.68-3.56 (m,8H); 3.52-3.39 (m,2H); 3.17-3.09 (m, 1H);2.97-2.90 (m, 1H); 2.35-2.27 (m,2H); 2.21-2.11 (m, 1H); 2.07-1.95(M,2H); 1.88-1.44 (m,12H) MS: 422 (M+H)⁺.

EXAMPLE 27

In a manner analogous to that described in the first paragraph ofExample 1, from 0.222 g of 1-[2(R orS)-(benzyloxycarbamoyl)-2-phthalimidoethyl]-3-cyclobutylpropionyl]piperidineprepared in a manner analogous to that described in Example l(i)-(ix)using N-(bromomethyl)-phthalimide, there was obtained 0.013 g of1[3-cyclobutyl-(2(R)-[1(R orS)-(hydroxycarbamoyl)-2-phthalimidoethyl]propionyl]piperidine(diastereoisomer 1) in the form of a white solid.

nmr (MeOD): 7.87-7.75 (m.4H); 3.83 (dd, J=14.8,1H); 3.66-3.58 (m,3H);3.53-3.45 (m, 1H); 3.35-3.25 (m, 1H); 3.20-3.12 (m, 1H); 3.04-2.97 (m,1H); 2.23-2.11 (m, 1H); 2.08-1.95 (m,2H); 1.89-1.41 (m,12H); MS: 428(M+H)⁺

The following Examples illustrate pharmaceutical preparations containingthe hydroxamic acid derivatives provided by the present invention:

Example A

Tablets containing the following ingredients may be produced in aconventional manner:

    ______________________________________                                        Ingredient              Per tablet                                            ______________________________________                                        Hydroxamic acid derivative                                                                            10.0 mg                                               Lactose                 125.0 mg                                              Corn starch             75.0 mg                                               Talc                    4.0 mg                                                Magnesium stearate      1.0 mg                                                Total weight            215.0 mg                                              ______________________________________                                    

Example B

Capsules containing the following ingredients may be produced in aconventional manner:

    ______________________________________                                        Ingredient              Per capsule                                           ______________________________________                                        Hydroxamic acid derivative                                                                            10.0 mg                                               Lactose                 165.0 mg                                              Corn starch             20.0 mg                                               Talc                    5.0 mg                                                Capsule fill weight     200.0 mg                                              ______________________________________                                    

We claim:
 1. Compounds of the formula ##STR8## wherein R¹ representscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;R² represents asaturated 5- to 8-membered monocyclic or bridged N-heterocyclic ring,which N-heterocyclic ring is attached via the N atom and when it ismonocyclic, optionally contains NR⁴, O, S, SO or SO₂ as a ring memberand/or is optionally substituted on one or more C atoms by hydroxy,lower alkyl, lower alkoxy, oxo, ketalized oxo, amino, mono(loweralkyl)amino, di(lower alkyl) amino, carboxy, lower alkoxycarbonyl,hydroxymethyl, lower alkoxymethyl, carbamoyl, mono(loweralkyl)-carbamoyl, di(lower alkyl)carbamoyl or hydroxyimino; R³represents a 5- or 6-membered N-heterocyclic ring which (a) is attachedvia the N atom, (b) optionally contains N, O and/or S, SO or SO₂ as aadditional ring member, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other C atoms by lower alkyl oroxo and/or on any additional N atom(s) by lower alkyl or aryl; R⁴represents hydrogen, lower alkyl, aryl, aralkyl or a protecting group; mstands for 1 or 2: and n stands for an integer from 1 to 4; lower alkylis a straight chain or branched-chain alkyl group of 1-6 carbon atoms;lower alkoxy is a straight chain or branched-chain alkoxy group of 1-6carbon atoms; and pharmaceutically acceptable salts thereof. 2.Compounds according to claim 1, whereinR¹ represents cyclopropyl,cyclobutyl or cyclopentyl; S R² represents a 5-, 6- or 7-memberedmonocyclic or bridged N-heterocyclic ring, which N-heterocyclic ring isattached via the N atom and when it is monocyclic, optionally containsNR⁴, O, S, SO or SO₂ as a ring member and/or is optionally substitutedon one or more C atoms by hydroxy, lower alkyl, lower alkoxy, oxo,ketalized oxo, amino, mono(lower alkyl)amino, di(lower alkyl) amino,carboxy, lower alkoxycarbonyl, hydroxymethyl, lower alkoxymethyl,carbamoyl, mono(lower alkyl)-carbamoyl, di(lower alkyl)carbamoyl orhydroxyimino; R³ represents a 5- or 6-membered N-heterocyclic ring which(a) is attached via the N atom, (b) optionally contains N, O and/or S asan additional ring member in a position or positions other than adjacentto the linking N atom, (c) is substituted by oxo on one or both C atomsadjacent to the linking N atom and (d) is optionally benz-fused oroptionally substituted on one or more other C atoms by lower alkyl oroxo and/or on any additional N atom(s) by lower alkyl or aryl; and R⁴represents hydrogen, lower alkyl or a protecting group.
 3. Compoundsaccording to claim 1, wherein R² represents 1-pyrrolidinyl, piperidino,4-aryl-1-piperazino, morpholino, tetrahydro-1,4-thiazin-4-yl,tetrahydro-1,4-thiazin-4-yl 1,1-dioxide, thiazolidin-3-yl,hexahydroazepino or octahydroazocino optionally substituted on one ormore C atoms by hydroxy, lower alkyl, lower alkoxy, ketalized oxo ormono(lower alkyl)-carbamoyl; or 3-azabicyclo[3.2.2]nonane.
 4. Compoundsaccording to claim 3, wherein R² represents piperidino.
 5. Compoundsaccording to claim 3, wherein R² is 4-hydroxypiperidino.
 6. Compoundsaccording to claim 1, wherein R³ represents a group of the formula##STR9## wherein R⁷ represents hydrogen, lower alkyl or aryl; Xrepresents --CO--, --CH₂ --, CH(lower alkyl)-, C(lower alkyl)₂ -,--NH--, --N(lower alkyl)-, or --O--; or,when R⁷ represents lower alkyland X represents -N(lower alkyl)-, the lower alkyl groups can be joinedto form a 5-, 6- or 7-membered ring.
 7. Compounds according to claim 1wherein m and n independently stand for
 1. 8. Compounds according toclaim 6, wherein m and n stand independently for
 1. 9.1-[3-Cyclopropyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine.10. 1-[3-Cyclopropyl-2-(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.11. 1-[3-Cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine.12. 1-[3-Cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.13. 1-[3-Cyclopentyl-2[(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-piperidinol.14. 1-[3-Cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine.15. A compound according to claim 1, wherein said compound is selectedfrom the group consisting of:1-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine.4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazineS,S-dioxide, 4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,4-[3-cyclohexyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]tetrahydro-1,4-thiazine,3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-5,5-dimethyl-N-propyl-4(R)-thiazolidinecarboxamide,4-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine,3-[3-cyclopentyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-N,5,5-trimethyl-4(R)-thiazolidinecarboxamide,4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-phenylpiperazine,4-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]morpholine.1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]pyrrolidine,8-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-1,4-dioxa-8-azaspiro[4,5]decane,1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]-4-methoxypiperidine,1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]octahydroazocine.1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(5,5-dimethyl-2,4-dioxo-3-oxazolidinyl)ethyl]propionyl]piperidine,1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]hexahydroazepine,1-[3-cyclobutyl-2(R)-[2-(hexahydro-1,3-dioxopyrazolo[1,2-a][1,2,4]triazol-2-yl)-1Ror S)-(hydroxycarbamoyl)ethyl]propionyl]piperidine and1-[3-cyclobutyl-2(R)-[1(R orS)-(hydroxycarbamoyl)-2-phthalimido-ethyl]propionyl]piperidine.